A genetic association between 8q24 sequence variants and prostate cancer risk was initially reported in 2006 and has been consistently replicated in several confirmation studies, including our study utilizing a large hospital-based case/control population from Johns Hopkins Hospital. While the association is the most convincing genetic finding in prostate cancer to date, many important questions remain regarding the complete picture of PCa genetic association at 8q24, the role of 8q somatic gains in the context of the genetic association, and whether a specific gene is implicated by the association. The overall hypothesis of this study is that germline and somatic genetic variants at 8q24 are associated with PCa risk. Specifically, we hypothesize that 1) multiple germline variants at 8q24 are associated with PCa risk and aggressiveness in European Americans and in African Americans;2) germline and somatic genetic changes at 8q24 have a joint effect on PCa risk and aggressiveness;and 3) 8q24 genetic variants affect PCa risk by altering gene expression in the flanking regions (cis-effect) and elsewhere in the genome (trans-effect). To test these hypotheses, we have assembled a research team from The Wake Forest University Center for Human Genomics and Johns Hopkins Hospital (JHH), and will combine our strengths in genetic association studies, somatic DNA analyses, and RNA/protein analyses. We have a unique opportunity to test our hypothesis regarding germline and somatic changes because of the large number of frozen prostate tissues in European Americans (N=400) and African Americans (N=400) available in the JHH. We have two specific aims. First, we will test the joint effect of implicated germline risk variants and somatic genetic changes at 8q24 on PCa risk and aggressiveness of the disease among these 800 tumors. Second, we will identify cis- or trans-effects of 8q24 risk variants on gene expression in prostate tissues by assessing correlation between the germline and somatic 8q24 variants and RNA/protein expression of genes in the 8q24 flanking region and elsewhere in the genome. Results from our study will improve our understanding of the most prominent genetic finding to date and may have important implications in disease prediction, diagnosis, and treatment. PUBLIC HEALTH RELEVANCE: In this study we will combine two major research methods, allowing us to simultaneously examine inherited genetic changes and acquired genetic changes in tumors. The goal will be to use these approaches to understand the role of 8q24 genetic variants in prostate cancer risk. Because the association between 8q24 genetic variants and prostate cancer is the most convincing association finding to date, our study has an excellent opportunity to advance our knowledge in the etiology, diagnosis, and treatment of prostate cancer.